Coprecipitation of Class II NSAIDs with Polymers for Oral Delivery

Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently administered orally with modified-release formulations. The attainment of modified-release drugs is commonly achieved through the coprecipitation of the active principle with a biodegradable polymeric carrier in the form of micro or nanoparticles. In this review, some coprecipitation studies of three highly prescribed NSAIDs (in particular, ibuprofen, ketoprofen, and diclofenac sodium) have been analyzed. The techniques employed to micronize the powder, the polymers used, and the main results have been classified according to the type of release required in different categories, such as delayed, immediate, prolonged, sustained, and targeted release formulations. Indeed, depending on the pathology to be treated, it is possible to achieve specific therapeutic objectives, ensuring that the drug is released at a higher or lower dissolution rate (if compared to conventional drugs) and/or at a different time and/or in a specific site of action.


Introduction
Pain and swelling are commonly mitigated using anti-inflammatory drugs, divided into two broad categories: corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs). Corticosteroids are steroid hormones produced in the adrenal cortex of vertebrates or synthetically. They are effective in reducing inflammation, particularly in the treatment of ocular problems [1], pulmonary diseases [2], and hepatitis [3]; considering the side effects linked to their administrations, it is recommended to use them in low doses and for short periods [4]. For these reasons, in the case of not particularly severe inflammations, patients prefer to use NSAIDs which can be purchased, in most cases, without a prescription. The mechanism of action of NSAIDs is based on the inhibition of cyclooxygenase enzymes (COX); pain and inflammation are reduced by restraining the formation of prostaglandins [5]. It is well known that COX exists as three isoforms: cyclooxygenase-1 (COX-1) is constitutive, typically expressed in cells and present, for example, in the endothelium, stomach and kidney; cyclooxygenase-2 (COX-2) is a form not always functional inside cells, which is induced by proinflammatory cytokines and endotoxin; cyclooxygenase-3 (COX-3) is believed to be centrally located, although many of its characteristics and functions remain currently ununderstood [6]. Considerations concerning the latter form will, therefore, be excluded from this review paper.
Some NSAIDs are COX-1 selective, some are non-selective, and others are COX-2 selective. NSAIDs are extensively used for their analgesic, antipyretic and anti-inflammatory properties and treat many inflammatory conditions or pain, such as headaches, toothache, soft tissue injuries, rheumatoid arthritis, osteoarthritis, etc. [7][8][9]. Recently NSAIDs, in particular ibuprofen, have been widely used in the home management of non-serious cases of COVID-19 [10,11], in therapies involving the use of NSAIDs and antioxidant compounds or vitamin complexes [12][13][14]. One of the main limitations of the use of NSAIDs is linked Given the vastness of the topic and considering that many NSAIDs are characterized by low solubility and high permeability, this review focuses on some BCS class II NSAIDs frequently prescribed or used by patients. The purpose of this review is linked to the need for an analysis that allows the identification of possible formulations not still present on the market, which could complement the already existing ones with reduced side effects. The formulation of new products could also expand the offer by addressing the problem that has recently arisen regarding the shortage of some drugs.

NSAIDs + Polymer Coprecipitation
Different techniques have been employed to coprecipitate an NSAID with a polymer carrier. Depending on the application, it is essential to correctly choose the carrier to obtain the drug's release at the desired speed and/or to a specific site of action. Indeed, the release of the active principle strongly depends on the carrier's affinity with water: hydrophilic polymers, such as PVP, can be used to enhance the drug dissolution rate; hydrophobic polymers, such as zein, can be used when a prolonged release is desired; pH-sensitive polymers, such as Eudragit, can be used for a targeted drug release [19][20][21]. This review is organized into subsections dedicated to three widely used NSAIDs; the published papers are classified as follows: (a) ibuprofen; (b) ketoprofen; (c) diclofenac sodium. In particular, ibuprofen is a non-selective drug towards COX-1 and COX-2; ketoprofen is COX-1 selective, whereas diclofenac sodium is COX-2 selective. Furthermore, attention has been focused on the type of formulations in terms of drug release for these three active ingredients. It is known that the release of a drug can be controlled by acting on the: -time of release (for example, delayed, repeated, or pulsatile release drugs); -dissolution rate (reduction or increase of the dissolution rate, obtaining prolonged or immediate release formulations); Given the vastness of the topic and considering that many NSAIDs are characterized by low solubility and high permeability, this review focuses on some BCS class II NSAIDs frequently prescribed or used by patients. The purpose of this review is linked to the need for an analysis that allows the identification of possible formulations not still present on the market, which could complement the already existing ones with reduced side effects. The formulation of new products could also expand the offer by addressing the problem that has recently arisen regarding the shortage of some drugs.

NSAIDs + Polymer Coprecipitation
Different techniques have been employed to coprecipitate an NSAID with a polymer carrier. Depending on the application, it is essential to correctly choose the carrier to obtain the drug's release at the desired speed and/or to a specific site of action. Indeed, the release of the active principle strongly depends on the carrier's affinity with water: hydrophilic polymers, such as PVP, can be used to enhance the drug dissolution rate; hydrophobic polymers, such as zein, can be used when a prolonged release is desired; pH-sensitive polymers, such as Eudragit, can be used for a targeted drug release [19][20][21]. This review is organized into subsections dedicated to three widely used NSAIDs; the published papers are classified as follows: (a) ibuprofen; (b) ketoprofen; (c) diclofenac sodium. In particular, ibuprofen is a non-selective drug towards COX-1 and COX-2; ketoprofen is COX-1 selective, whereas diclofenac sodium is COX-2 selective. Furthermore, attention has been focused on the type of formulations in terms of drug release for these three active ingredients. It is known that the release of a drug can be controlled by acting on the: -time of release (for example, delayed, repeated, or pulsatile release drugs); -dissolution rate (reduction or increase of the dissolution rate, obtaining prolonged or immediate release formulations); -place (release in specific regions, e.g., gastrointestinal tract).
In the literature analysis, a classification was made into delayed, fast, prolonged (or sustained), controlled, and targeted release formulations. Delayed release occurs when the drug is released after a latency period. Included in this group are gastro-resistant tablets, which allow the passage of the drug through the stomach, where gastric juices could usually destroy the polymer carrier and where the drug release can cause severe damage. Immediate-release dosage is a mechanism that delivers a drug without delaying or prolonging dissolution. Prolonged-release pharmaceutical forms are preparations that slowly release the active principle over time, extending the duration of its effectiveness compared with a conventional pharmaceutical form. Sustained-release pharmaceutical forms are preparations that, like the previous ones, slowly release the drug over time, but compared to them, they release the drug at a predetermined rate maintaining constant API concentration for a specific time. Targeted release dosage is a mechanism that delivers the drug to a specific target in the body.

Ibuprofen
Ibuprofen first came to market about 50 years ago. It has a balanced safety profile due to its non-selectivity between COX-1 and COX-2 [22]. In any case, as well as other NSAIDs, prolonged use of this active ingredient can damage the upper gastrointestinal tract [23]. For this reason, it has been frequently coupled with a lipidic or polymeric carrier. In Table 1, the attempts to process ibuprofen in the presence of a carrier are listed, together with the technique used to process the NSAID, the morphology obtained, and the main results.  Yields in the range 70 ÷ 87% and encapsulation efficiencies higher than 80%; pH-sensitive release patterns evaluated through in vitro release tests in SGF and SIF [36] As it is possible to observe from Table 1, in many cases, ibuprofen is contained in lipid nanoparticles, which can be distinguished into two categories: solid lipid nanoparticles (SLN), constituted of a solid lipid matrix, and nanostructured lipid carriers (NLC), composed by a blend of a solid lipid and a liquid lipid. The disadvantage of the latter is that, upon administration, they are rapidly removed from the salivary liquid, as they do not remain in contact with the oral mucosa for a sufficient time. To avoid this drawback, they can be incorporated into mucoadhesive preparations, such as the hydrogels proposed by Marques et al. [29]. As shown in Figure 2, if properly designed, mucoadhesive hydrogels allow a sustained release of the active ingredient; gels with free ibuprofen (HG-C free ibu and HG-P free ibu) released the drug faster in comparison with the gels containing NLC.
lipid nanoparticles, which can be distinguished into two categories: solid lipid nanoparticles (SLN), constituted of a solid lipid matrix, and nanostructured lipid carriers (NLC), composed by a blend of a solid lipid and a liquid lipid. The disadvantage of the latter is that, upon administration, they are rapidly removed from the salivary liquid, as they do not remain in contact with the oral mucosa for a sufficient time. To avoid this drawback, they can be incorporated into mucoadhesive preparations, such as the hydrogels proposed by Marques et al. [29]. As shown in Figure 2, if properly designed, mucoadhesive hydrogels allow a sustained release of the active ingredient; gels with free ibuprofen (HG-C free ibu and HG-P free ibu) released the drug faster in comparison with the gels containing NLC.  In vitro release profile of ibuprofen from hydrogels with Carbopol ® 980 (HGd-CS), hydrogels with polycarbophil (HGd-PS), Carbopol ® 980 gel with free ibuprofen (HG-C free ibu) and polycarbophil gel with free ibuprofen (HG-P free ibu). Reprinted with permission from [29]. Copyright© 2017 Elsevier.
Different carriers, such as gelatin, chitosan, soy protein, and some others, have been used in the literature to protect ibuprofen and tune its release.
The authors have often stressed the importance of the process yield and encapsulation efficiency to avoid wasting active ingredients. The chosen polymers generally favored the achievement of sustained releases of the active principle [29,[31][32][33][34] to reduce the dosing frequency and the adverse gastrointestinal reactions induced by ibuprofen. In some cases, in vitro release kinetics were evaluated in simulated gastrointestinal conditions (pH 1.2 and 6.8), and pH-sensitive release patterns were observed.
The different techniques used by the authors allow for obtaining particles with different dimensions and distributions. For example, spherical microparticles of quite regular sizes are obtained through spray drying, as shown in the exemplificative image in Figure 3. Different carriers, such as gelatin, chitosan, soy protein, and some others, have been used in the literature to protect ibuprofen and tune its release.
The authors have often stressed the importance of the process yield and encapsulation efficiency to avoid wasting active ingredients. The chosen polymers generally favored the achievement of sustained releases of the active principle [29,[31][32][33][34] to reduce the dosing frequency and the adverse gastrointestinal reactions induced by ibuprofen. In some cases, in vitro release kinetics were evaluated in simulated gastrointestinal conditions (pH 1.2 and 6.8), and pH-sensitive release patterns were observed.  Reprinted with permission from [31]. Copyright© 2012 Elsevier.

Ketoprofen
Ketoprofen is an NSAID with analgesic, anti-inflammatory, and antipyretic properties synthesized in 1968. It is indicated to relieve mild-to-moderate pain conditions such as dental pain, dysmenorrhea, post-operative pain, and chronic problems such as osteoarthritis and rheumatoid arthritis [37,38]. Adverse events induced by ketoprofen use are headache, cardiovascular reactions, dermatological issues, gastric and duodenal irritation, ulceration, and bleeding [39,40]. To reduce the side effects and suitably modulate the re- Reprinted with permission from [31]. Copyright© 2012 Elsevier.

Ketoprofen
Ketoprofen is an NSAID with analgesic, anti-inflammatory, and antipyretic properties synthesized in 1968. It is indicated to relieve mild-to-moderate pain conditions such as Polymers 2023, 15, 954 6 of 15 dental pain, dysmenorrhea, post-operative pain, and chronic problems such as osteoarthritis and rheumatoid arthritis [37,38]. Adverse events induced by ketoprofen use are headache, cardiovascular reactions, dermatological issues, gastric and duodenal irritation, ulceration, and bleeding [39,40]. To reduce the side effects and suitably modulate the release of the drug, this is associated with a suitable carrier to form a composite system. Similar to what has already been observed for ibuprofen, different techniques and carriers have been used to process this active ingredient. The main results are summarized in Table 2.   Depending on the application, different polymers have been used: to obtain an immediate or rapid effect (for example, in the case of headaches), polymers that speed up the release of the API have been chosen [43,48], to treat inflammatory diseases influenced by circadian rhythms, the aim of targeting early morning symptoms other polymers have been selected [41], or to obtain the release in specific areas of the body, polymers such as eudragits which are pH-dependent have been utilized [48]. In other cases, coprecipitated particles have been obtained, but no dissolution tests were performed. For example, Widyastama and Kumiati [61] optimized the sonication time and surfactant concentration to obtain ketoprofen/chitosan/alginate nanoparticles.
In some cases, coupling a polymer with an inorganic material has given rise to the obtainment of multifunctional products. For example, Attia et al. [46] used an in situ oxidative chemical polymerization of pyrrole coupled with a reduction of ferric chloride in the presence of ketoprofen (with or without a surfactant). The final product is a multifunctional system, which could act as a nanocarrier for drug molecules and a contrasting agent.
Ketoprofen was also coupled with microRNAs, post-transcriptional regulators of gene expression, which are small endogenous non-coding RNAs. Their presence can induce the improvement of the therapeutic effect of ketoprofen when rheumatoid arthritis is treated. Indeed, Yu et al. [56] performed in vivo pharmacodynamics experiments using ketoprofen co-loaded with microRNA-124 into PLGA microspheres (which exemplificative images are reported in Figure 4), observing that ketoprofen could significantly reduce inflammation of the joints and microRNA-124 could reduce bone damage. In addition, they had remarkably advanced activity over the delivery of either microRNA-124 or ketoprofen in suppressing adjuvant-induced arthritis in rats.  In some cases, drugs derived from ketoprofen have been used, such as its lysinated form. This drug can be used for lung inflammation that often occurs in patients with cystic fibrosis. Stigliani et al. used co-spray drying by precipitating ketoprofen lysinate with leucine to obtain microparticles that can reach the deepest airways [62].
A further step with respect to in vitro dissolution tests was made by some authors who also carried out in vivo tests [41,56,60]. In some cases, the powders obtained have also been tested on animals. For example, Boppana et al. [60] have prepared pH-sensitive interpenetrated network polyspheres to achieve intestinal targeted delivery of ketoprofen, avoiding API side effects such as ulcer formation, erosion of gastric mucosa, and hemorrhages. The authors conducted tests on rats, administering ketoprofen as it is and ketoprofen contained in the polyspheres. Stomach histopathological studies had shown ulcers (1.97 mm in size), hemorrhages, prominent mucosal erosion with congestion, edema, and perforations when ketoprofen alone was administered; on the contrary, in rats administered with pH-sensitive polyspheres, small ulcers of about 0.11 mm without perforation, congestion, hemorrhages, and necrosis were noticed. Pictures obtained through a binocular light microscope are reported in Figure 5. In particular, in Figure 5A, the stomach of control rats with signs of ulcer/hemorrhages is reported. In contrast, the analyses of the guts of rats treated with pristine ketoprofen or ketoprofen contained in pH-sensitive polyspheres are reported in Figure 5B,C, respectively. In some cases, drugs derived from ketoprofen have been used, such as its lysinated form. This drug can be used for lung inflammation that often occurs in patients with cystic fibrosis. Stigliani et al. used co-spray drying by precipitating ketoprofen lysinate with leucine to obtain microparticles that can reach the deepest airways [62].
A further step with respect to in vitro dissolution tests was made by some authors who also carried out in vivo tests [41,56,60]. In some cases, the powders obtained have also been tested on animals. For example, Boppana et al. [60] have prepared pH-sensitive interpenetrated network polyspheres to achieve intestinal targeted delivery of ketoprofen, avoiding API side effects such as ulcer formation, erosion of gastric mucosa, and hemorrhages. The authors conducted tests on rats, administering ketoprofen as it is and ketoprofen contained in the polyspheres. Stomach histopathological studies had shown ulcers (1.97 mm in size), hemorrhages, prominent mucosal erosion with congestion, edema, and perforations when ketoprofen alone was administered; on the contrary, in rats administered with pH-sensitive polyspheres, small ulcers of about 0.11 mm without perforation, congestion, hemorrhages, and necrosis were noticed. Pictures obtained through a binocular light microscope are reported in Figure 5. In particular, in Figure 5A, the stomach of control rats with signs of ulcer/hemorrhages is reported. In contrast, the analyses of the guts of rats treated with pristine ketoprofen or ketoprofen contained in pH-sensitive polyspheres are reported in Figure 5B,C, respectively.
avoiding API side effects such as ulcer formation, erosion of gastric mucosa, and hemorrhages. The authors conducted tests on rats, administering ketoprofen as it is and ketoprofen contained in the polyspheres. Stomach histopathological studies had shown ulcers (1.97 mm in size), hemorrhages, prominent mucosal erosion with congestion, edema, and perforations when ketoprofen alone was administered; on the contrary, in rats administered with pH-sensitive polyspheres, small ulcers of about 0.11 mm without perforation, congestion, hemorrhages, and necrosis were noticed. Pictures obtained through a binocular light microscope are reported in Figure 5. In particular, in Figure 5A, the stomach of control rats with signs of ulcer/hemorrhages is reported. In contrast, the analyses of the guts of rats treated with pristine ketoprofen or ketoprofen contained in pH-sensitive polyspheres are reported in Figure 5B,C, respectively.

Diclofenac Sodium
Diclofenac was patented in 1965 and came into medical use in 1988. It treats pain and inflammatory diseases, especially arthritis, rheumatoid arthritis, osteoarthritis, dental pain, menstrual pain, and endometriosis. An additional indication is the treatment of acute migraines and moderate postoperative or post-traumatic pain. In some cases, it is administered locally through transdermal delivery [63][64][65] or through in situ injections [66,67], but the most common method of administration is the oral one. The side effects Reprinted with permission from [60]. Copyright© 2019 Elsevier.

Morphology
Particles in the range from 87 ± 0.47 nm to 103 ± 0.26 nm; EE up to 99.03%; initial burst effect followed by a sustained release; arthritis was induced in rabbits, which were treated with intraarticular injections of the API, demonstrating a significant reduction in swelling [85] [89] As already observed in the previous sections, what is immediately noticeable when looking at Table 3 is the variety of polymeric carriers used to process the active ingredient (specifically, diclofenac sodium) to control temporal or distributional drug delivery. The category of polymers that appears to be most used is that of eudragit, which has the particularity of being pH-dependent, in many cases favoring the dissolution of the active ingredient in the intestinal tract. It also seems interesting to use poly electrolyte complexes, constituted by combining two polymers, of which one polymer is positively charged, and another is negatively charged. For example, Sandeep et al. [79] combined cationic guar gum, which has a net positive charge because of its trimethyl ammonium groups, with xanthan gum, with polyanionic properties due to carboxylic groups. These two polymers, despite their biodegradable character, cannot be used alone in the attainment of controlled-release formulations as both possess highly acidic or alkaline pH caused by the presence of anionic or cationic groups. When they react together, a novel poly electrolyte complex can be prepared to release the API in a controlled manner.
It can also be noted that depending on the techniques and operating conditions used, both nanoparticles and microparticles are obtained. Considering that the powders obtained are generally administered in the form of tablets or capsules, no particular advantage is observed in going down to very small sizes. Microparticles, therefore, could have the advantage of being easier to handle than nanoparticles. This allows easier recovery of the micronized material obtained.

Conclusions
This review focused on the coprecipitation of three NSAIDs with proper polymeric carriers to obtain controlled-release drugs. Various techniques and a wide range of polymers have been used to obtain powders that can be used for different purposes. In the case of ibuprofen and diclofenac sodium, coprecipitated particles were mainly obtained for the sustained or prolonged release of the active ingredient using chitosan and its derivatives, starch, ethyl cellulose, soy proteins, or zein as carriers. Ketoprofen, on the other hand, has been formulated for different purposes. In some cases, it has been coprecipitated with PVP (alone or combined with other polymers) or cyclodextrins to obtain rapid-release formulations; in other cases, delayed-release (with alginate and its derivatives) or sustainedrelease (using chitosan or PMMA) formulations were prepared. For all the APIs, it was also possible to note a wide use of pH-dependent polymers, such as eudragit, which avoid the dissolution of the active principle inside the stomach, allowing its release at intestinal pH. Some studies have stopped at the in vitro analysis of the dissolution of the active ingredients, while others have gone as far as studying the release with cells in vivo and on animals (mice or rabbits).
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.